Clinical research regulations in the United States
More actions
Hierarchy of legal authority in the United States
The U.S. legal framework follows a defined hierarchy of authority. At the highest level are federal statutes (primary law) enacted by Congress. These statutes establish broad legal requirements and delegate regulatory authority to federal agencies.
Under this delegated authority, federal agencies issue regulations that are codified in the Code of Federal Regulations [note 1] (CFR). CFR regulations constitute binding delegated law and are legally enforceable [note 2]. They provide detailed, operational requirements implementing statutory mandates through formal notice-and-comment rulemaking.
Below the CFR are agency guidance documents and compliance practices [note 3]. These do not have the force of law but describe how an agency interprets and applies CFR requirements in routine oversight, inspections, and regulatory review [note 4].
| Level of authority | Issuing body / source | Example | Legal status and role |
|---|---|---|---|
| Statutes (Acts of Congress) | Enacted by Congress and signed by the President | Federal Food, Drug, and Cosmetic Act | Primary law. Establish broad legal requirements and delegate regulatory authority to federal agencies |
| Regulations (Code of Federal Regulations) | Issued by federal agencies under authority granted by statutes; adopted through notice-and-comment rulemaking and codified in the CFR | 21 CFR Part 312 | Binding delegated law. Legally enforceable and subject to judicial review. Translate statutory mandates into detailed, operational requirements |
| Guidance documents and compliance policies | Issued by federal agencies as interpretive or policy statements | Informed Consent – Guidance for IRBs, Clinical Investigators, and Sponsors | Generally non-binding. Describe agency interpretation of statutes and regulations and outline current enforcement and compliance expectations |
Regulatory framework for human subjects research in the U.S.
Regulation of human subjects research in the United States is derived from two primary federal regulatory frameworks, depending on the nature of the research and the source of oversight. Depending on the study, research may be subject to both the Common Rule and FDA regulations.
1. Department of Health and Human Services (HHS) – The Common Rule
Research conducted or supported by U.S. federal agencies is governed by the Federal Policy for the Protection of Human Subjects, commonly known as the Common Rule [1].
The Common Rule is codified in the Code of Federal Regulations at 45 CFR 46 [2] and is administered by the U.S. Department of Health and Human Services (HHS) through the Office for Human Research Protections (OHRP).
Multiple federal Participating agencies [note 5] have adopted this framework for the protection of human research participants.
2. Food and Drug Administration (FDA) – FDA GCP
Clinical investigations involving products regulated by the U.S. Food and Drug Administration are governed by FDA regulations codified in Title 21 of the Code of Federal Regulations [3].
These regulations apply regardless of funding source and include requirements for the conduct of clinical investigations and the protection of human subjects.
Common Rule
The Common Rule is a set of regulations for the ethical conduct of research involving human subjects, and several U.S. federal agencies participate in enforcing these regulations. These are the agencies and departments that have agreed to follow the Common Rule [4]:
- Agency for International Development
- Department of Agriculture
- Bureau of Prisons, US Department of Justice
- Central Intelligence Agency
- Department of Commerce
- Consumer Product Safety Commission
- Department of Defense
- Department of Education
- Department of Energy
- Environmental Protection Agency
- Federal Bureau of Investigation, Department of Justice
- Department of Health and Human Services
- Department of Homeland Security
- Department of Housing and Urban Development
- Office of justice Programs, Department of Justice
- Department of Labor
- National Aeronautics and Space Administration
- National Science Foundation
- Office of the Director of National Intelligence
- Social Security Administration
- Department of Transportation
- Department of Veteran Affairs
FDA human research regulations
Rules governing human research are primarily found in Title 21 of the Code of Federal Regulations (CFR).
Current Good Manufacturing Practice (cGMP) regulations
- 21 CFR 211 - Current Good Manufacturing Practice for Finished Pharmaceuticals: standards for methods, facilities, and controls used in manufacturing, processing, packing, and holding of drug products
Regulations for drugs and biologics
- 21 CFR 312 - Investigational new drug application (IND): procedures and requirements for clinical investigations of drugs and biologics
- 21 CFR 314 - New Drug Application (NDA): review the data and decide whether to approve the drug for marketing
Regulations for medical devices
- 21 CFR 812 - Investigational Device Exemptions (IDE): requirements for clinical investigations of medical devices
- 21 CFR 814 - Premarket Approval of Medical Devices (PMA): clinical data demonstrating the safety and effectiveness of the device
General regulations for clinical trials
- 21 CFR 11 - Electronic Records and Electronic Signatures: criteria for electronic records and signatures to be considered equivalent to paper records and handwritten signatures
- 21 CFR 50 - Protection of Human Subjects: requirements for informed consent in clinical trials
- 21 CFR 54 - Financial disclosure by clinical investigators: requirements on financial transparency and conflict of interests
- 21 CFR 56 - Institutional Review Boards (IRBs): roles and responsibilities of IRBs in reviewing and approving clinical trials
Compliance requirements
Compliance is required with statutes and the CFR, while guidance reflects current agency interpretation rather than independent legal obligation.
Compliance with the Common Rule:
Required when the Department of Health and Human Services (HHS) or its agencies provide funding.
Compliance with FDA rules
Required when using FDA regulated products in research.
Institutional rules
If neither the Common Rule nor FDA rules apply, the institution conducting the research will impose its own rules. These are set via institutional review board (IRB) standard operating procedures (SOPs). Institutions may also choose to apply the Common Rule to any research conducted within their facilities.
Origin of rules governing human subjects protections and IRBs
Human subjects protections and IRBs are governed by rules from the Office for Human Research Protections. These rules are published in:
- 21 CFR 50 (human subjects protections)
- 21 CFR 56 (IRBs)
See also
Another relevant pages
References
- ↑ HHS description of the Common Rule, Federal Policy for the Protection of Human Subjects (“Common Rule”), OHRP 2025
- ↑ U.S. Department of Health and Human Services, Office for Human Research Protections, 45 CFR 46 Regulations, OHRP 2024
- ↑ FDA overview of clinical trial and human subject protection regulations, Regulations: Good Clinical Practice and Clinical Trials, FDA 2021
- ↑ Agencies and departments that have signed onto the Common Rule and their CFR numbers, Common Rule Departments and Agencies, OHRP 2025
External links
- Regulations: Good Clinical Practice and Clinical Trials, FDA 2021
- Regulatory Authority, NIAID ClinRegs 2025
- Comparison of FDA and HHS Human Subject Protection Regulations, FDA 2018
Footnotes
- ↑ The Code of Federal Regulations (CFR) is the codification of all federal agency rules that implement statutes. It is created through a public rulemaking process under the Administrative Procedure Act. Wex legal dictionary, Legal Information Institute
- ↑ Regulations in the CFR have the force of law because Congress authorizes agencies to issue them under statute. What’s a Regulation vs. a Law: A Guide to How Government Rules Work, GovFacts 2025
- ↑ Agency guidance documents represent interpretations or policy positions, and they do not have independent legal force in the same way as CFR regulations. Agency Use of Guidance Documents, Congress.gov 2021
- ↑ FDA publishes proposed and final rules in the Federal Register; after a final rule is promulgated, it is codified into the CFR FDA Rules and Regulations, FDA 2024
- ↑ The term “Participating agencies” refers to the federal agencies that have adopted the Common Rule